1. Field
The present invention relates to heterocyclic sulfonamides, methods for their manufacture, and their use as medicaments, especially for treating chronic heart failure.
2. Description
Sulfonamides are known inhibitors of endothelin receptors. See, for example, EP 0 713 875. There is a need for endothelin receptor inhibitors that have high antagonistic potency and achieve high plasma levels following oral administration.
The subject invention provides compounds of formula: 
wherein
R1 is pyridyl, pyridyl substituted with lower alkyl, pyridyl substituted with lower alkenyl, thiazolyl, thiazolyl substituted with lower alkyl, or thiazolyl substituted with lower alkenyl;
and pharmaceutically usable salts of such compounds.
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to by construed as limiting.
The present invention relates to compounds of the formula (I) 
wherein
R1 is a heterocyclic residue selected from pyridyl and thiazolyl, where said heterocyclic residue may optionally be substituted with lower alkyl or lower alkenyl;
and pharmaceutically acceptable salts thereof.
The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier and/or adjuvant.
Furthermore the present invention relates to the use of such compounds for the preparation of medicaments for the treatment or prophylaxis of disorders which are associated with abnormal vascular tone and endothelial dysfunction.
The present invention also relates to processes for the preparation of the compounds of formula (I).
In addition, the present invention relates to a method for the prophylactic and/or therapeutic treatment of disorders that are associated with abnormal vascular tone and endothelial dysfunction, which method comprises administering a compound of formula (I) to a human being or an animal.
The sulfonamides of the present invention are inhibitors of endothelin receptors. They can accordingly be used for the treatment of disorders which are associated with abnormal vascular tone and endothelial dysfunction. EP 0 713 875 discloses sulfonamide compounds as endothelin receptor inhibitors. However, the compounds of the present invention have a high antagonistic potency in vitro and show unexpectedly high plasma levels following oral administration.
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term xe2x80x9clower alkylxe2x80x9d refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
The term xe2x80x9clower alkenylxe2x80x9d refers to a lower alkyl group containing one or more double bond(s) in the alkylene chain.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non-toxic to living organisms. It also includes salts with inorganic or organic bases such as alkali salts like sodium and potassium salts, alkaline earth metal salts like calcium and magnesium salts, N-methyl-D-glutamine salts and salts with amino acids like arginine, lysine and the like.
More particularly, the present invention relates to compounds of the above formula (I), wherein
R1 is a heterocyclic residue selected from pyridyl and thiazolyl, where said heterocyclic residue may optionally be substituted with lower alkyl or lower alkenyl. The term xe2x80x9clower alkylxe2x80x9d preferably means methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl or t-butyl, more preferably methyl, ethyl or isopropyl, still more preferably methyl or isopropyl, most preferably methyl. The term xe2x80x9clower alkenylxe2x80x9d preferably means vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl or 3-butenyl, more preferably vinyl, 1-propenyl, allyl and isopropenyl, most preferably isopropenyl.
Preferred heterocyclic residues in R1 are 2-pyridyl and 2-thiazolyl, most preferred is 2-pyridyl. In a preferred embodiment, the heterocyclic residues in R1 are substituted with lower alkyl or lower alkenyl, with lower alkyl being preferred.
Particularly preferred residues R1 are 5-methyl-pyridine-2-yl, 5-isopropyl-pyridine-2-yl, 5-isopropenyl-pyridine-2-yl and 5-methyl-thiazol-2-yl. More preferred are 5-methyl-pyridine-2-yl, 5-isopropyl-pyridine-2-yl and 5-isopropenyl-pyridine-2-yl. Still more preferred are 5-methyl-pyridine-2-yl and 5-isopropyl-pyridine-2-yl. Most preferred is 5-methyl-pyridine-2-yl.
Particularly preferred compounds of formula (I) are 5-methyl-pyridine-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]- amide, 5-isopropyl-pyridine-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide, 5-isopropenyl-pyridine-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide and 5-methyl-thiazole-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]- amide.
More particularly preferred compounds of formula (I) are 5-methyl-pyridine-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide and 5-isopropyl-pyridine-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide, most preferred is 5-methyl-pyridine-2-sulfonic acid[6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]- amide.
The compounds of formula (I) can be prepared in analogy to known processes or processes described below and summarized in the following schemes 1 and 2:
4,6-Dichloro-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine (described in EP 0 799 209) can be transformed to the intermediate of formula (III)xe2x80x94according to scheme 1xe2x80x94on reaction with an appropriate sulfonamide of formula (II), wherein R1 is as defined in claim 1, in a suited solvent such as DMSO or DMF at room temperature or at elevated temperature and in the presence of a suited base such as potassium carbonate.
The corresponding sulfonamides can also be applied in above reaction in form of their re-formed sodium or potassium salts.
Compounds of formula (III) can be further transformed to compounds of formula (I) by treatment with sodium methylate in a solvent such as methanol. 
The heterocyclic sulfonamides of formula (II) are either already known in the literature, prepared in a manner analogous to established procedures and/or can be derived from corresponding mercapto derivatives in analogy to a known reaction sequence comprising oxidation with Cl2 in an acidic aqueous medium, such as diluted aqueous HCl, to yield the corresponding sulfonyl chlorides which can be transformed with liquid ammonia or aqueous ammonium hydroxide to the sulfonamides. The corresponding sodium or potassium salts can be obtained on treatment with sodium or potassium alkoxide in an appropriate solvent such as methanol.
Alternatively, compounds of formula (I) can be preparedxe2x80x94according to scheme 2xe2x80x94starting from 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-1-oxide (preparation described in EP 0 799 209) in a reaction sequence analogous to that of scheme 1, to give compounds of formula (V).
Pyridine-N-oxide reduction of compounds of formula (V) can be accomplished with a reagent system such as TiCl4/NaI in analogy to a method described in Chem. Ber. 123, 647 (1990), or with a trialkylsilyl chloride (for example, t-butyldimethylsilyl chloride) in the presence of a suited base, such as triethylamine, and with acetonitrile as a solvent. Other methods for pyridine-N-oxide deoxygenation are known per se and comprise, for example, catalytic hydrogenation or reduction with reducing agents such as trivalent phosphorus compounds or metals in acid. The conditions are a matter of choice and are readily determinable by the skilled artisan. 
The intermediates of above formula (III) and formula (V), wherein R1 is as defined above 1, preferably wherein R1 is 5-methyl-pyridine-2-yl or 5-isopropyl-pyridine-2-yl, and the pharmaceutically acceptable salts thereof are new and are also subject of the present invention.
The inhibitory activity of the compounds of formula (I) on endothelin receptors can be demonstrated using the test procedures described hereinafter:
I. Inhibition of Endothelin Binding to Recombinant Human ETA Receptors Expressed in Baculovirus-infected Insect Cells
A cDNA coding for human ETA receptors of human placenta was cloned (M. Adachi, Y.-Y. Yang, Y. Furuichi and C. Miyamoto, BBRC 180, 1265-1272) and expressed in the Baculovirus-insect cell system. Baculovirus-infected insect cells from a 23 l fermenter are centrifuged off (3000xc3x97g, 15 minutes, 4xc2x0 C.) 60 hours after the infection, re-suspended in Tris buffer (5 mM, pH 7.4, 1 mM MgCl2) and again centrifuged. After a further re-suspension and centrifugation the cells are suspended in 800 ml of the same buffer and freeze-dried at xe2x88x92120xc2x0 C. The cells disintegrate when the suspension in this hypotonic buffer mixture is thawed. After a repeated freeze-drying/thawing cycle the suspension is homogenised and centrifuged (25000xc3x97g, 15 minutes, 4xc2x0 C.). After suspension in Tris buffer (75 mM, pH 7.4, 25 mM MgCl2, 250 mM sucrose) 1 ml aliquots (protein content about 3.5 mg/ml) are stored at xe2x88x9285xc2x0 C.
For the binding assay, the freeze-dried membrane preparations are thawed and, after centrifugation at 20xc2x0 C. and 25000 g for 10 minutes, re-suspended in assay buffer (50 mM Tris buffer, pH 7.4, containing 25 mM MnCl2, 1 mM EDTA and 0.5% bovine serum albumin). 100 xcexcl of this membrane suspension containing 70 xcexcg of protein are incubated with 50 xcexcl of 125I-endothelin (specific activity 2200 Ci/mMol) in assay buffer (25000 cpm, final concentration 20 pM) and 100 xcexcl of assay buffer containing varying concentrations of test compound. The incubation is carried out at 20xc2x0 C. for 2 hours or at 4xc2x0 C. for 24 hours. The separation of free and membrane-bound radio-ligands is carried out by filtration over a glass fibre filter. The inhibitory activity of compounds of formula (I) determined in this test procedure is given in Table 1 as the IC50, i.e. as the concentration [nM] which is required to inhibit 50% of the specific binding of 125I-endothelin.
II. Inhibition of Endothelin-induced Contractions in Isolated Rat Aorta Rings
Rings with a length of 5 mm were cut out from the thorax aorta of adult Wistar-Kyoto rats. The endothelium was removed by lightly rubbing the internal surface. Each ring was immersed at 37xc2x0 C. in 10 ml of Krebs-Henseleit solution in an isolated bath while gassing with 95% O2 and 5% CO2. The isometric stretching of the rings was measured. The rings were stretched to a pre-tension of 3 g. After incubation for 10 minutes with the test compound or vehicle cumulative dosages of endothelin-1 were added. The activity of the test compound was ascertained by the observed shift to the right of the dosage-activity curve of endothelin-1 in the presence of different concentrations of antagonist. This shift to the right (or xe2x80x9cdose ratioxe2x80x9d, DR) corresponds to the quotient from the EC50 values of endothelin-1 in the presence and in the absence of antagonist, with the EC50 value denoting the endothelin concentration required for a half-maximum contraction.
The corresponding pA2 value, which is a measure of the activity of the test compound, was calculated using a computer programme according to the following equation from the xe2x80x9cdose ratioxe2x80x9d DR for each individual dosage-activity curve.
pA2=log(DRxe2x88x921)xe2x88x92log(antagonist-concentration)
The EC50 of endothelin in the absence of test compounds is 0.3 nM.
The pA2 values obtained with compounds of formula (I) are given in the following Table 3.
III. Pharmacokinetics of the Endothelin Receptor Antagonists
The pharmacokinetics of the newly synthesised endothelin receptor antagonists were assessed in Wistar rats. The test compounds were dissolved in DMSO at a concentration of 5 mg/mL and administered orally by gavage at a dose of 1 mL/kg body weight corresponding to 5 mg/kg body weight. Two rats were administered per test compound. Blood samples were collected from the retro-orbital sinus at 1 and 5 h post dose in one rat, and at 3 and 7 h post dose in the other rat. In addition a terminal 24 h blood sample was collected from both rats by heart puncture. Blood was collected on EDTA-NaF. Plasma was derived by centrifugation at 2000 g at +4xc2x0 C. for 15 min. Plasma samples were assayed for active drug related material with a bioassay, based on the binding competition of tested compounds and 125I ET-1 on recombinant ETA receptors. Quantitation of plasma samples was by comparison to a calibration curve build up from control rat plasma spiked with known concentrations of the test compounds. Selected findings are summarised in the following table:
On the basis of their capability of inhibiting endogenous endothelin binding, the compounds of formula (I) can be used as medicaments for the treatment of disorders that are associated with abnormal vascular tone and endothelial dysfunction.
Therefore, the application field of the compounds of formula (I) could be heart failure (acute and chronic), systemic and pulmonary hypertension, acute ischaemic coronary syndrome, angina pectoris, renal failure (acute and chronic), organ transplant (e.g. liver, heart, kidney), cyclosporin nephrotoxicity, vasospastic disease (subarachnoid haemorrhage but also haemorrhagic and non-haemorrhagic stroke, Raynaud syndrome), peripheral artery occlusive disease, prevention of restenosis after stent or balloon angioplasty, septic shock or multiple organ failure as that occurring in intensive care, asthma, chronic obstructive pulmonary disease, gastric and duodenal ulcus, liver cirrhosis, pancreatitis (acute and chronic), inflammatory bowel disease, fibrosis, atheriosclerosis, obesity, glaucoma, prostatic adenoma, migraine, erectile dysfunction, adjunct to cancer therapy as well as other disorders associated with endothelin activities.
The compounds of formula (I) can also be administered in combination with antihypertensive drugs, antiarrhythmics, anti angina, antithrombotic and lipid lowering agents as well as antioxidants.
It will be appreciated that the compounds of formula (I) in this invention may be derivatised at functional groups to provide prodrug derivatives that are capable of conversion back to the parent compounds in vivo. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.
As mentioned earlier, medicaments containing a compound of formula (I) are also an object of the present invention, as is a process for the manufacture of such medicaments, which process comprises bringing one or more compounds of formula (I) and, if desired, one or more other therapeutically valuable substances into a galenical administration form.
The pharmaceutical compositions may be administered orally, for example in the form of tablets, coated tablets, dragxc3xa9es, hard or soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be carried out rectally, for example using suppositories; locally or percutaneously, for example using ointments, creams, gels or solutions; or parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally, using for example injectable solutions. Furthermore, administration can be carried out sublingually or as opthalmological preparations or as an aerosol, for example in the form of a spray.
For the preparation of tablets, coated tablets, dragxc3xa9es or hard gelatine capsules the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients for tablets, dragees or hard gelatine capsules include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof.
Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid or liquid polyols etc.; according to the nature of the active ingredients it may however be the case that no excipient is needed at all for soft gelatine capsules.
For the preparation of solutions and syrups, excipients which may be used include for example water, polyols, saccharose, invert sugar and glucose.
For injectable solutions, excipients which may be used include for example water, alcohols, polyols, glycerine, and vegetable oils.
For suppositories, and local or percutaneous application, excipients which may be used include for example natural or hardened oils, waxes, fats and semi-solid or liquid polyols.
The pharmaceutical compositions may also contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for the variation of osmotic pressure, buffers, coating agents or antioxidants. As mentioned earlier, they may also contain other therapeutically valuable agents.
It is a prerequisite that all adjuvants used in the manufacture of the preparations are non-toxic.
Preferred forms of use are intravenous, intramuscular or oral administration, most preferred is oral administration. The dosages in which the compounds of formula (I) are administered in effective amounts depend on the nature of the specific active ingredient, the age and the requirements of the patient and the mode of application. In general, dosages of about 0.01-10 mg/kg body weight per day come into consideration.
The following Examples shall illustrate preferred embodiments of the present invention but are not intended to limit the scope of the invention. Of the abbreviations used therein, MeOH signifies methanol, AcOEt signifies ethyl acetate, DMF signifies dimethylformamide, RT signifies room temperature, HPLC signifies high performance liquid chromatography, TLC signifies thin layer chromatography, ISN signifies Ion Spray Mass Spectrometryxe2x80x94negative mode, EI signifies Electron Impact Mass Spectrometry and M signifies molecular mass.